Lipophilic hydroxylated acid, its use in cosmetics and pharmacy, and its process of preparation

ABSTRACT

The invention relates to new lipophilic hydroxylated acids wherein said lipophilic hydroxylated acid comprises a hydrophobic hydrocarbon chain having from 7 to 30 carbon atoms grafted onto the hydroxyl functional group and/or the acid functional group of the lipophilic hydroxylated acid via a covalent bond chosen from the group consisting of an ester bond on the hydroxyl functional group, an anhydride bond on the acid functional group and an amide bond on the acid functional group, provided that, in the case of an amide bond, this hydrophobic hydrocarbon chain consists of an alkyl radical having from 10 to 30 carbon atoms resulting from a monoamine, or a combination of these bonds. These new derivatives are useful as active ingredient of cosmetic or pharmaceutical compositions and as emulsifying agents.

This is a division of prior application Ser. No. 08/557,154, filed Feb.16, 1996, now U.S. Pat. No. 5,869,069 which is a continuation-in-partapplication of Ser. No. 08/354,228, filed Dec. 12, 1994, now abandoned,and also a § 371 national phase of international applicationPCT/FR95/00984 filed Jul. 21, 1995.

FIELD OF THE INVENTION

The present invention relates essentially to a new lipophilichydroxylated acid, to its use in cosmetics and in pharmacy, and to itsprocess of preparation.

BACKGROUND OF THE INVENTION SUMMARY OF THE PRIOR ART

It is known, from the article by Van Scott et al. in Arch. Dermatol.,Vol. 110, October 1974, pages 586-590, to use a-hydroxylated acids intopical preparations in order to carry out a particularly effectivekeratolysis in the treatment of ichthyosis and of dry skins.

Likewise, Middleton has described, in J. Soc. Cosmet. Chem., 25 (1974),pages 519-534, a skin cream containing lactic acid or sodium lactate inorder to reduce the dry skin forming scales in the corneal layer orstratum corneuln.

The use of α-hydroxylated acid derivatives, by topical use, for treatinga dry skin associated with eczema has also been published by Malcolm W.Greaves in Cosmetics and Toiletries, Vol. 105, October 1990, pages61-64. This article emphasises, on page 61, right-hand column, secondlast paragraph, that, like urea, α-hydroxylated acids have beenrestricted in use due to their irritant nature. This article relates tothe use of a composition containing a methoxypropylgluconamide with alower acidity. This compound is also the subject of European PatentApplication EP-A-0,338,565 of Revlon. This European application relatesto a compound of formula: ##STR1## in which formula p is an integer from1 to 4, (C_(n) H_(2n)) is a straight- or branched-chain alkyl bridge inwhich n is an integer from 1 to 6, and (C_(m) H_(2m-1)) is a straight-or branched-chain alkyl group in which m is an integer from 1 to 6.

These compounds are therefore amide derivatives of an at leastdihydroxylated acid necessarily containing an ether chain, whichcompounds are different from those developed and used in the context ofthe present invention.

Greaves et al. have observed that the compounds described in thisdocument EP-A-0,338,565 have little effectiveness as keratolytic agents,hence the necessity to use them at very high concentrations. Inaddition, this keratolytic property cannot be modified as it is verysimilar from one product to another.

In contrast, in the context of the present invention, new compounds wereable to be discovered whose activity can be modified from a verypowerful activity to a much gentler activity.

The document EP-A-0,273,202, Van Scott et al., describes additives basedon hydroxycarboxylic acid which promote the topical actions oftherapeutic agents present in an amount ranging from 0.01 to 99 weight %of the total composition.

The α-hydroxylated acids, their salts and their lactone form describedin the document EP-A-0,273,202 have a very strong keratolytic power whenthey are used at high concentrations and at acid pH values. However,under such conditions of use, they are poorly tolerated by the skinsurface and cause stinging, red blotches and inflammatory phenomena,which greatly restricts their use under such conditions.

In the present invention, new products have been discovered which arenon-irritant in a wide pH range which can range from a very acidic pH inthe region of 3 or 3.5 to a neutral pH of the order of 7, even when theyare tested at very high concentrations such as 100%.

Hydroxylated acid amides obtained with a monoamine or a diamine whichcan in particular contain a C₁ -C₈ alkyl radical are also known from thedocuments Van Scott U.S. Pat. Nos. 4,105,783 and 4,197,316. In thecontext of the invention, when it concerns amides, the latter areobtained with a monoamine having a C₁₀ -C₃₀ fatty alkyl radical.

The document Revlon EP-A-0,447,064 also relates to alkoxyamides of thetype of those described in the above document EP-A-0,338,565 which aredifferent from those developed and used in the context of the presentinvention.

Various other documents relate to esters of the hydroxylated acid acidfunctional group which are different from those developed and used inthe context of the present invention. These documents relating to estersare WO-A-95/03032, EP-A-0,599,819 Van Scott, EP-A-0,273,202;EP-A-0,521,647 Unilever in which citric acid fatty acid esters aredescribed in which the acid functional groups of the citric acid arenecessarily substituted by ester bonds with an ester substitution groupR₁, R₂ and R₃. The hydroxyl functional group of the citric acid can besubstituted by an acyl group R₄ which is preferably an acyl group havingfrom 2 to 4 carbon atoms. In the context of the invention, ester bondson the acid group of the hydroxylated acid are not sought for and anester bond from the hydroxyl functional group of the hydroxylated acidcomprises at least 7 carbon atoms.

The application from l'Oreal EP-A-0,526,302 relates to2,5-dihydroxybenzenecarboxylic acid salts or esters in which the estersare produced on the acid functional group which are different from thosedeveloped and used in the context of the present invention. Mention maybe made, as other esters of the acid functional group of thehydroxylated acid, of the documents Unilever EP-A-0,282,289;EP-A-0,261,812; the document U.S. Pat. No. 5,302,377 of Croda; thedocument U.S. Pat. No. 4,078,147 Ukai; Swiss Patents CH-A-449,852 and443,565 of the Laboratoires Prod'Hyg, French Patent HenkelFR-A-2,390,160; and the document Henkel DE-4,033,565.

Mention will further be made, as amide, of German documentDE-A-1,543,929 which describes amides of2,4-dihydroxy-3,3-dimethylbutyric acid from a C₅ to C₃₀hydroxyalkylamine or alkoxyalkylamine, i.e. a different amine from thealkylamines of the invention having C₁₀ -C₃₀.

Moreover, topical compositions intended for skin treatment based onsalicylic acid derivatives are also known from the documentFR-A-2,581,542 of l'Oreal. These derivatives correspond to the formula:##STR2## in which R represents a hydrocarbon chain which can have up to17 carbon atoms and R' can represent a hydroxyl functional group or anester functional group of the formula ##STR3## containing from 2 to 16carbon atoms, it being possible for this chain to be saturated orunsaturated and for n to have a value between 0 and 14 (see thedescription and claim 1 in particular).

The preferred compounds are those in which R' denotes a hydroxylfunctional group and R an alkyl group having from 3 to 11 carbon Atoms(claim 2 and page 3, lines 10 to 20).

It emerges from this formula that these derivatives are necessarilysubstituted in position 5 of the phenyl ring by a radical containing aketone functional group which appears to be the determining factor inproviding a keratolytic activity greater than that of salicylic acid, asindicated in the description on page 2, lines 5 to 10.

In the context of the present invention, new hydroxylated acidderivatives have been discovered which are particularly active andnon-irritant, including salicylic acid derivatives other thanderivatives substituted in position 5 of the phenyl ring of thesalicylic acid which are described in this document.

In addition, it has been discovered that the derivatives of theinvention also exhibited a significant emulsifying power which makes itpossible to use them as the sole emulsifying agent, that is to say usedalone, or as a coemulsifying agent, making it possible to reduce theamount of other emulsifying agents.

Moreover, the 5-keto-substituted derivatives of salicylic acid describedin the above document FR-A-2,581,542 have the major disadvantage thatthe ketone bond cannot be hydrolyzed enzymatically. In addition,although an ester functional group is provided on the hydroxylfunctional group, the only derivative prepared is the acetyl ester inPreparation Example G which appears, from the pharmacology tests ofTables I and II, to be less active than the free derivatives.

In fact, this document FR-A-2,581,542 teaches those skilled in the artthe necessity of using derivatives substituted in position 5 of thesalicylic acid by a ketone bond and the fact that the hydroxylfunctional group of the salicyclic acid must be free.

This is confirmed by the document FR-A-2,607,498 of l'oreal whichrelates to lipophilic quaternary ammonium salicylates in which thehydroxyl functional group of the salicylic acid is unsubstituted andwhich always contains, in position 5, the radical bonded by a ketonebond to the phenyl ring, this salicylate being in the ionic form byvirtue of the presence of a quaternary ammonium which comes to becoupled to the COO⁻ functional group of the acid. Consequently, thesedocuments dissuade those skilled in the art from searching for salicylicacid derivatives other than the 5-keto-substituted derivatives, that isto say carrying a radical bonded by a ketone bond.

These compounds, however, have the disadvantage that they are nothydrolyzable, either spontaneously or under the action of skin orbacterial enzymes.

Document EP-A-0,378,936 also uses the same salicylic acid derivatives tocarry out skin ageing treatment, which derivatives have the samedisadvantages of not being hydrolyzable, either spontaneously or underthe action of skin or bacterial enzymes.

Moreover, the document EP-A-0,433,104 of Unilever relates to a shampoocomposition containing 2-hydroxyalkanoic acid in combination with abuffering agent forming a coacid, so that the pH of the composition ispreferably between 3 and 5.

Further, the document EP-A-0,413,528 of Yu and Van Scott relates toamphoteric compositions and to polymer forms of α-hydroxy acid and totheir therapeutic use in treating dry skins, acne, keratosis, psoriasis,eczema, ageing blotches, wrinkles, pallid skin, hyperpigmented skin,hyperkeratinized skin, inflammatory dermatoses or skin changesassociated with age and as skin-cleaning product. In fact, as emergesfrom the list given on pages 29 and 30, it concerns the same hydroxyacids as those which are described in the document EP-A-0,273,202analyzed above. These products are poorly tolerated by the skin surfaceand cause stinging, red blotches and inflammatory phenomena whichgreatly restrict their use.

A similar document further consists of the document EP-A-0,508,324 filedby Yu and Van Scott for treating signs of ageing of the skin, of thenails and of the hair.

Finally, the document EP-A-0,585,170 is also a l'Oreal document relatingto a composition for treating acne containing the quaternary ammoniumsalt of the 5-ketone derivative of salicylic acid with a quaternaryammonium ion, encapsulated in liposome-type vesicles.

It is thus observed that the prior art demonstrates that intensiveresearch is being carried out regarding the use of α-hydroxylated acidsin cosmetic or pharmaceutical compositions but that none of thesolutions proposed has been capable of simultaneously solving theproblem of tolerance of these products by the skin surface, the acidsbeing too harmful, and the problem of their modifiable effectiveness, aswell as of their biocompatibility in being degradable or hydrolyzablespontaneously or under the action of skin or bacterial enzymes. Inaddition, their affinity with respect to lipid constituents of theepidermis remains limited.

SUMMARY OF THE INVENTION

The aim of the present invention is to solve the new technical problemconsisting in providing new products which can be used as cosmetic orpharmaceutical and/or dermatological products having a greater affinitywith respect to lipid constituents of the epidermis, in particular thestratum corneum, which are non-irritant and which have a modifiableeffectiveness.

Another main aim of the present invention is to solve the new technicalproblem consisting in providing new products which can be used ascosmetic or pharmaceutical and/or dermatological products havingexcellent biocompatibility, especially in being hydrolyzable eitherspontaneously or under the action of skin or bacterial enzymes.

Another aim of the present invention is to solve these new technicalproblems according to a solution which makes it possible to providecompounds having good keratolytic activity in being capable of reachingthe desmosomes and the nascent layers of the stratum corneum.

A further aim of the present invention is to solve the new technicalproblem consisting in providing a solution which makes it possible toprovide products having anti-acne and/or anti-wart and/or anti-eczema isand/or anti-psoriasis and/or anti-dandriff and/or anti-dry-skin and/oranti-wrinkle and/or anti-age activity, without significant irritantpower.

A further aim of the present invention is to solve the new technicalproblem consisting in providing a solution which makes it possible toproduce new agents which improve skin moisturizing, elasticity andcohesion as well as new depigmenting agents, without significantirritant power.

Another main aim of the present invention is to solve the new technicalproblem consisting in providing a solution which makes it possible toproduce new products which have an excellent emulsifying ability whichmakes it possible to use them either as the sole emulsifying agent or asa coemulsifying agent, thus making it possible to reduce theconcentration of other emulsifying agents used, in particular during themanufacture of cosmetic or pharmaceutical and/or dermatologicalcompositions.

It has been found entirely unexpectedly that all these technicalproblems could be solved by providing new hydroxylated acid derivatives,described below. It has also been discovered that the effectiveness ofthese new derivatives was increased when these derivatives are used whenpresent in the final reaction mixture with the unreacted starting acids.

Thus, according to a first aspect, the present invention provides newlipophilic hydroxylated acids, said hydroxylated acids comprising atleast one hydroxyl functional group and at least one acid functionalgroup, wherein said lipophilic hydroxylated acid comprises a hydrophobichydrocarbon chain having from 7 to 30 carbon atoms grafted onto thehydroxyl functional group and/or the acid functional group of thehydroxylated acid via a covalent bond chosen from the group consistingof an ester bond on (the hydroxyl functional group, an anhydride bond onthe acid functional group, an amide bond on the acid functional group,provided that, in the case of an amide bond, this hydrophobichydrocarbon chain consists of an alkyl radical having from 10 to 30carbon atoms resulting from a monoamine, or a combination of thesebonds.

According to a first embodiment, this lipophilic hydroxylated acid isone wherein the hydroxylated acid, before grafting of the abovementionedhydrophobic hydrocarbon chain, comprises a saturated or unsaturated,straight or branched or cyclic chain having from 2 to 30 carbon atoms.

According to another embodiment, this lipophilic hydroxylated acid isone wherein the grafting of the abovementioned hydrophobic hydrocarbonchain is carried out by reaction of a hydroxylated acid with a monoaminecontaining an alkyl radical containing a straight, branched or cyclicchain having from 10 to 30 carbon atoms or, in the case of the formationof ester bonds on the hydroxyl functional group of the hydroxylated acidor of an anhydride bond on the acid functional group of the hydroxylatedacid, with an acid comprising from 7 to 30 carbon atoms, it beingpossible for said hydrophobic hydrocarbon chain of the acid to besaturated or unsaturated, linear or branched or cyclic, without anotherfunctional group on its skeleton or with other functional groups, inparticular acid, alcohol and/or amine functional group(s).

According to yet another embodiment, this lipophilic hydroxylated acidis one wherein said hydroxylated acid is mono- or polyhydroxylated andis a monoacid or a polyacid.

According to another embodiment, this lipophilic hydroxylated acid isone which has the hydroxylated acid, before grafting of the hydrophobichydrocarbon chain, comprises from 2 to 18 carbon atoms.

According to another embodiment, this lipophilic hydroxylated acid isone wherein the hydroxylated acid, before grafting of the abovementionedhydrophobic hydrocarbon chain, is chosen from the group consisting of anα-hydroxylated acid, such as glycolic acid, lactic acid, malic acid,tartaric acid, gluconic acid, citric acid, methyllactic acid, mandelicacid, atrolactic acid, phenyllactic acid, glyceric acid, benzilic acid,α-hydroxybutanoic acid, α-hydroxyhexanoic acid, α-hydroxyheptanoic acidor α-hydroxyoctanoic acid; a β-hydroxylated acid, such as salicylic acidor serine; and a polymer or a copolymer of this hydroxylated acid, ortheir mixtures.

Naturally, as is very easily understood by those skilled in the art,this list is not in any way exhaustive since all hydroxylated acids canbe used in the context of the invention. It is a further advantage ofthe invention that acids having a hydroxyl functional group a long wayfrom the acid functional group can advantageously be used. The inventionthus covers the use of any hydroxylated acid without limitation.However, the hydroxylated acids currently preferred are the acids whichhave a starting hydrocarbon chain of 2 to 30 carbon atoms and morepreferably of 2 to 18 carbon atoms.

According to another embodiment, this lipopholic hydroxylated acid isone which has a ratio by weight of the hydroxylated acid to thehydrophobic chain of 0.05 to 10, and preferably of 0.05 to 2.

According to a second aspect, the present invention also relates to theuse of the lipophilic hydroxylated acid as active ingredient of acosmetic composition or of a dermatological and/or pharmaceuticalcomposition and/or as emulsifying agent.

According to a specific embodiment, the use is one wherein theabovementioned lipophilic hydroxylated acids, as active principle,exhibit a keratolytic activity, a chemical exfoliation activity deep inthe skin, which makes it possible to improve the subsequent enetrationby other active ingredients, a stimulating activity of the cellfunctions, which improves the elasticity and the cohesion of the skin, adepigmenting activity, an anti-wrinkle or anti-age activity, amoisturizing activity which makes it possible to treat dry andichthyotic skins, or an anti-acne, anti-wart, anti-eczema,anti-psoriasis or anti-dandruff activity.

According to yet another specific embodiment, the use is one wherein theabovementioned lipophilic hydroxylated acids constitute particularlyadvantageous emulsifying agents, where they are used as sole emulsifyingagent or as a coemulsifying agent. Moreover, when they are used asactive principle at relatively high concentrations, it is not necessary,due to their emulsifying activity, to use other emulsifying agents,which constitutes an unexpected technical effect which is particularlyadvantageous in the formulation of the cosmetic, pharmaceutical and/ordermatological composition in so far as the usual emulsifying agentsalways present risks of bioincompatibility.

According to a third aspect, the present invention also covers acomposition chosen from the group consisting of a cosmetic,pharmaceutical and/or dermatological composition, wherein it comprises,as active ingredient and/or as emulsifying agent, at least onelipophilic hydroxylated acid mentioned above.

According to a specific embodiment, the composition is one wherein theproportion of lipophilic hydroxylated acid is between 0.001 weight % and50 weight % of the final composition, preferably between 1 weight % and20 weight % of the final composition.

According to another specific embodiment, the composition is one whereinthe abovementioned lipophilic hydroxylated acid is the reaction productof a hydroxylated acid chosen from the group consisting of malic acid,glycolic acid, gluconic acid, salicylic acid, lactic acid, serine, aglycolic acid polymer, a lactic acid polymer or a glycolic acid andlactic acid copolymer and of a compound comprising the abovementionedhydrophobic hydrocarbon chain chosen from the group consisting of ahalide or anhydride of stearic acid, palmitic acid, myristic acid,lauric acid, octanoic acid, decanoic acid, undecylenic acid, undecanoicacid, oleic acid, linolenic acid, linoleic acid or acetic acid or oftheir succinic or maleic derivatives.

According to another embodiment, the composition is one wherein theabovementioned lipophilic hydroxylated acid is the reaction product of ahydroxylated acid with a monoamine containing an alkyl radicalcontaining a straight, branched or cyclic chain having from 10 to 30carbon atoms.

According to a fourth aspect, the present invention further covers aprocess for the manufacture of the abovementioned lipophilichydroxylated acid, wherein it comprises the reaction of a hydroxylatedacid with a halide or an anhydride of an acid comprising a hydrophobichydrocarbon chain having from 2 to 30 carbon atoms or with a monoaminecontaining an alkyl radical containing a straight, branched or cyclicchain having from 10 to 30 carbon atoms.

According to a specific embodiment, the process is one wherein theabovementioned hydroxylated acid, or acid halide or anhydride, ormonoamine are as defined above.

According to another specific embodiment, the manufacturing process isone wherein, for the grafting of a hydrophobic hydrocarbon chainoriginating from an acid, a halide or an anhydride of the acid is usedas starting material.

According to another specific embodiment, the process is one wherein,for the grafting of a hydrophobic hydrocarbon chain originating from amonoamine, use is made as starting material of a monoamine which isreacted with the hydroxylated acid in the presence of a catalyst, of abifunctional agent or of an enzyme.

This bifunctional agent is well known to those skilled in the art.Particularly preferred bifunctional agents are a carbodiimide, inparticular N-(3-dimethyl-aminopropyl)-N'-ethylcarbodiimidehydrochloride, oxalyl chloride, diphenylphosphoryl azide,propanephosponic anhydride or any other agent commonly used as couplingagent during linear peptide syntheses.

According to yet another specific embodiment, the process is one whereinan enzymatic grafting of a hydrophobic hydrocarbon chain onto thehydroxylated acid is carried out. Such enzymes capable of carrying outthis grafting are well known to those skilled in the art. For example,mention could be made of an industrial lipase, for example the enzymecommercially available under the trade name Lipozyme®, manufactured bythe company Novo®. This enzymatic grafting is particularly advantageousfor grafting amines.

According to another specific embodiment, the process is one wherein thereaction takes place at a temperature between approximately 0° C. andapproximately 100° C., preferably at room temperature, in aqueous mediumor an organic solvent.

It should be noted that the grafting reactions can be carried out athigh temperature (between 80° and 100° C.) to give higher yields butinvolve more stresses and risks of deterioration of the products.

Moreover, the relative proportions of the hydroxylated acid to thesubstance introducing the hydrophobic hydrocarbon chain can vary withinwide limits. Thus, the relative proportions by weight, used during thereaction, can vary from 5/95 to 95/5, preferably from 5/95 to 50/50.

Moreover, it can be advantageous first of all to neutralize thehydroxylated acid to a pH in the region of neutrality, that is to say inthe region of 7. It is also possible to provide for maintaining the pHof the reaction at a basic value during the reaction.

In this case, it is possible to adjust the pH continuously either usinga strong base of the NaOH or KOH type or to provide a buffer such asphosphate, carbonate, borate or citrate or the addition of a moleculesuitable for continuously trapping the acid manufactured during thereaction, such as triethanolamine (TEA), cyclohexylamine, and the like.

Moreover, after the reaction, it can also be advantageous to adjust thepH according to the applications envisaged, generally betweenapproximately 2 and approximately 7. It can also be advantageous tolyophilize the final reaction mixture in order to obtain a lyophilizedproduct containing all the products of the reaction mixture, namely thelipophilic hydroxylated acid mixed with the unreacted startingmaterial(s), in particular the acids and/or monoamines, which isparticularly advantageous in the context of the invention.

Sterilization can optionally be carried out conventionally, especiallyin the context of a cosmetic, pharmaceutical or dermatological use, forexample by β- or γ-rays.

By virtue of the invention, new lipophilic hydroxylated acids areobtained which possess a greater affinity with respect to the lipophilicconstituents of the stratum corneum and are thus capable of becomingintegrated more easily throughout the thickness of the stratum corneum.

In addition, by virtue of the grafting of a lipophilic group onto thehydroxylated acids, via ester bonds on the hydroxyl functional groupand/or amide and anhydride bonds on the acid functional group of thehydroxylated acid, bonds are used which are hydrolyzable by enzymaticsystems naturally present in the skin, such as lipases and proteases,and at the surface of the latter, such as enzymes released bysaprophytic micro-organisms present in very large numbers on the skin.

Thus, the new compounds of the invention make it possible, by a naturalhydrolysis, progressively to release the hydroxylated acids, which makesit possible to obtain the use of their activity at the site where thehydroxylated acid will have been conveyed or transported by thelipophilic grafting and to obtain a delayed effect while maintainingthis activity over long periods of time, which makes it possibleunexpectedly to reduce the concentrations of use.

It could also be observed that the products according to the inventionare essentially non-irritant, in contrast to the hydroxylated acidspreviously used.

The products of the invention also exhibit new activities which havebeen stated above.

In particular, these products are particularly effective emulsifyingagents. Thus, the invention also covers a composition comprising, asemulsifying agent, at least one lipophilic hydroxylated acid, inparticular at a concentration of between 0.1 weight % and 50 weight % ofthe final composition, preferably between 1 weight % and 20 weight % ofthe final composition.

In the context of the invention, it is preferred that the products arenot purified, that is to say that they are present in the reactionmixture comprising the unreacted starting acids, which means that only apart (from 5 to 90 mol %, and most often 10 to 30 mol %) of thehydroxylated acids are converted to esters, to amides or to anhydrides,the other part being complexed more or less intensively to thehydrophobic chains via ionic bonds, bonds of Van der Waals type,hydrophilic bonds and hydrophobic bonds. In the case where the processof preparation involves the use of a non-aqueous solvent, thisnon-aqueous solvent generally being incompatible with a cosmetic,pharmaceutical and/or dermatological use, this solvent will usually beremoved.

They then take part, in the pure state or, preferably, in the crudemanufacturing state, that is to say in the final reaction mixturecomprising the unreacted starting acids, in the formulations ofcosmetic, pharmaceutical and/or dermatological preparations.

The lipophilic hydroxylated acids according to the invention canadvantageously be presented in a dry form, in particular a lyophilizedform.

In the context of the present description and claims, the terms"monoamine containing an alkyl radical having from 10 to 30 carbonatoms" relate to an amine comprising a single amine functional groupwhich is monosubstituted or disubstituted by an alkyl radical havingfrom 10 to 30 carbon atoms, that is to say having a linear, branched orcyclic fatty chain. Such monoamines containing a fatty chain are wellknown to the person skilled in the art and laurylamine or stearylaminewill be mentioned by way of example.

According to a fifth aspect, the present invention also relates to amethod for keratolytic treatment, for cosmetic or therapeutic use, onregions of the skin having need thereof, comprising the application tosaid regions of the skin of a keratolytic effective amount of at leastone lipophilic hydroxylated acid compound which is the reaction productof a hydroxylated acid having at least one acid functional group and atleast one hydroxyl functional group with a hydrophobic hydrocarboncomponent having a hydrophobic hydrocarbon chain having from 7 to 30carbon atoms, grafted onto one or both of said hydroxyl and acidfunctional groups via a covalent bond chosen from the group consistingof an ester bond on the hydroxyl functional group, an anhydride bond onthe acid functional group and an amide functional group on the acidfunctional group, provided that, in the case of an amide bond, thishydrophobic hydrocarbon chain consists of an alkyl radical having from10 to 30 carbon atoms resulting from a monoamine, or a combination ofthese bonds.

Preferred embodiments of the method are clearly apparent to a personskilled in the art from the description taken in its entirety andincluding all the claims which are incorporated by reference.

According to a sixth aspect, the invention also relates to a treatmentmethod, for cosmetic or therapeutic use, for chemical exfoliation of theskin, for stimulating the cells of the skin, for improving theelasticity and the cohesion of the skin, for depigmenting the skin, formoisturizing the skin, or for producing an anti-wrinkle effect on theskin, an anti-aging effect on the skin, an anti-acne effect on the skin,an anti-wart effect, an anti-eczema effect, an anti-psoriasis effect onthe skin and an anti-dandruff effect on the regions of the hair and ofthe scalp, comprising the application to said skin, to the hair or tothe scalp having need thereof of an effective amount of a lipophilichydroxylated acid compound which is the reaction product of ahydroxylated acid having at least one acid functional group and at leastone hydroxyl functional group with a hydrophobic hydrocarbon componenthaving a hydrophobic hydrocarbon chain having from 7 to 30 carbon atomsgrafted onto one or both of said hydroxyl and acid functional groups viaa covalent bond chosen from the group consisting of an ester bond on thehydroxyl functional group, an anhydride bond on the acid functionalgroup and an amide functional group on the acid functional group,provided that, in the case of an amide bond, this hydrophobichydrocarbon chain consists of an alkyl radical having from 10 to 30carbon atoms resulting from a monoamine, or a combination of thesebonds. Similarly, preferred embodiments of the method are clearlyapparent to the person skilled in the art from the description taken inits entirety and including all the claims which are incorporated forreference.

Other aims, characteristics and advantages of the invention will becomeclearly apparent in the light of the explanatory description which willfollow, made with reference to the examples below, given simply by wayof illustration and which could in no way limit the scope of theinvention. However, it is to be observed that these examples clearlycontain, for those skilled in the art, general information andconsequently make it possible to support claims of general scope. In allthe examples, the percentages are given by weight, except when otherwiseindicated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows standard curves which can be obtained when keratolytictests are carried out. These curves are obtained by plotting the time,in days, on the abscissa and the color intensity, as measured by achromameter, in this case a Minolta®, on the ordinates. The colorintensity on day T₀, reference C0, is obtained by applying an emulsioncontaining dihydroxyacetone (DRA) as coloring agent as described inExample 20. Curve I is obtained by measuring the color intensity withthe chromameter as a function of the time expressed in days, without anyspecific intervention. Curve II is obtained by applying one of thekeratolytic formulations tested, expressed in the same way. Thedifference between the two curves, expressed as ΔE, measures thekeratolytic strength of the keratolytic formulation as a function oftime. The sum of the ΔE values, which represents the area or surfacedefined between Curves I and II, represents the overall keratolyticperformance of the keratolytic formulation tested and is the subject ofFIG. 3;

FIG. 2 represents a bar chart example obtained with a keratolyticcomposition comprising a lipophilic compound of Example 1 of theinvention (I₂) based on a stearic acid/malic acid anhydride and estermixture, corresponding to 4% of free malic acid, as a function of thetime, expressed in days, on the abscissa and also as a function of thecolor intensity, expressed as color difference ΔE, on the ordinate, inaccordance with FIG. 1; and

FIG. 3 represents the test results obtained with various compounds ofthe invention I₁, I₂ and I₃, as detailed in Example 19, as a function ofthe acid concentration expressed as equivalent free acid and thekeratolytic activity, on the ordinate, expressed in the form of area orsurface resulting from the sum of all the color differences ΔE betweenCurves I and II plotted in FIG. 1 and as explained in relation to FIG.1.

DESCRIPTION OF THE EXAMPLES Example 1 of the Invention

Lipophilic Hydroxylated Acid Comprising a Stearic Acid and Malic AcidEster and Anhydride Mixture

100 g of malic acid are placed in 500 ml of demineralized water. Thereaction mixture is adjusted to a pH of 11 with a sodium hydroxidesolution (NaOH, 12N). 100 g of stearic acid chloride are slowly addedwith very vigorous stirring of Ultraturrax or Silverson type (10,000 to20,000 rpm).

The pH moves in a few tens of minutes from a value of 11 to a valueclose to 1, when no buffer is added to the reaction mixture.

After a reaction time of approximately 1 h, the whole mixture isneutralized to a pH of between 2.0 and 7.0 with a sodium hydroxidesolution (NaOH, 12N).

The whole mixture can then preferably be lyophilized and then optionallysterilized by γ- or β-rays.

The product exists in the form of a very white pulverulent powder whichcan be placed both in the aqueous phases and in the oily phases ofcosmetic preparations.

Part of the hydroxylated acid (malic acid) exists in the form of a fattyacid ester and anhydride and part, which has not reacted, is in a formtightly complexed via hydrogen bonds and via Van der Waals bonds.

This product therefore comprises stearic acid and malic acid esters andanhydrides, the anhydride functional group being between the acidfunctional group of the malic acid and the acid functional group of thestearic acid and the ester functional group being obtained between theacid functional group of the stearic acid and the hydroxyl functionalgroup of the malic acid. This grafting takes place both on the acidfunctional group and on the hydroxyl functional group. Moreover, theproduct obtained also comprises the unreacted starting acids, optionallyin the salt form, depending on the final pH after neutralization and onthe pK_(a) of the acids used.

It has been discovered according to the present invention that the finalreaction mixture can be used as is, without specific purification orseparation, to constitute a cosmetic or pharmaceutical or dermatologicalactive principle and/or as emulsifying agent, which constitutes adetermining advantage of the present invention.

Harmlessness tests, based on an absence of skin and eye irritation, werecarried out with this product and form the subject of Example 17.

Example 2 of the Invention

Lipophilic Hydroxylated Acid Comprising a Palmitic Acid and GlycolicAcid Ester and Anhydride Mixture

The same grafting process is used as that described in Example 1 butglycolic acid is used in place of malic acid and palmitic acid chloridein place of stearic acid chloride.

A palmitic acid and glycolic acid ester and anhydride mixture is thusobtained, as well as the unreacted starting acids. The final crudereaction mixture can be used as is.

Example 3 of the Invention

Lipophilic Hydroxylated Acid Comprising a Lauric Acid and Gluconic AcidEster and Anhydride Mixture

The same process is used as that described in Example 1, except thatgluconic acid is used in place of malic acid and lauric acid chloride isused in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 4 of the Invention

Lipophilic Hydroxylated Acid Comprising an Undecylenic Acid andSalicylic Acid Ester and Anhydride Mixture

By carrying out the reaction according to the process described inExample 1, but using salicylic acid in place of malic acid andundecylenic acid chloride in place of stearic acid chloride, the titlecompound is obtained as a mixture with the unreacted starting acids.

The final reaction mixture can be used as is.

Example 5 of the Invention

Lipophilic Hydroxylated Acid Comprising a Mixture of Esters andAnhydrides of Palmitic and Oleic Acid and of Polymers of Various Acids

Example 5a

Grafting a Palmitic and Oleic Acid Chloride Mixture (80/20 w/w) onto aGlycolic Acid Polymer

The reaction is carried out as described in Example 1 but a glycolicacid polymer of molecular weight 10,000 to 700,000 D is used in place ofmalic acid and a palmitic and oleic acid chloride mixture (80/20 w/w) isused in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 5b

Reaction Product of a Lactic Acid Polymer with a Palmitic and Oleic AcidChloride Mixture (80/20 w/w)

The reaction is carried out as described in Example 1, except that alactic acid polymer, molecular weight 10,000 to 700,000 D, is used inplace of malic acid and a palmitic and oleic acid chloride mixture(80/20 w/w) is used in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 5c

Reaction Product of a Lactic Acid and Glycolic Acid Copolymer with aPalmitic and Oleic Acid Chloride Mixture (80/20 w/w)

The reaction is carried out as described in Example 1, except that alactic acid and glycolic acid copolymer of molecular weight 10,000 to100,000 D is used and a palmitic and oleic acid chloride mixture (80/20w/w) is used in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 6 of the Invention

Lipophilic Hydroxylated Acid Comprising a Stearic and Linolenic Acid andSerine Ester and Anhydride Mixture

The reaction is carried out as described in Example 1, except thatserine is used in place of malic acid and a stearic and linolenic acidchloride mixture (80/20 w/w) is used in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 7 of the Invention

Lipoohilic Hydroxylated Acid Comprising an Acetic Acid and Tartaric AcidEster and Anhydride Mixture

The reaction is carried out as described in Example 1, except thattartaric acid is used in place of malic acid and acetic anhydride isused in place of stearic acid chloride.

The final reaction mixture can be used as is.

Example 8 of the Invention Example 8a

Lipophilic Hydroxylated Acid Comprising a Succinic Acid and TartaricAcid Ester and Anhydride Mixture

The reaction is carried out as described in Example 1 but tartaric acidis used in place of malic acid and succinic anhydride is used in placeof stearic acid chloride.

The final reaction mixture can be used as is.

Example 8b

The reaction is carried out as described in Example 1, except thattartaric acid is used in place of malic acid and maleic anhydride isused in place of stearic acid chloride.

As for all the other examples, the final reaction mixture can be used asis.

Example 9 of the Invention

Lipophilic Hydroxylated Acid Comprising a Stearic Acid and Lactic AcidEster and Anhydride Mixture

Whereas the reaction takes place in aqueous solvent in the precedingExamples 1 to 8, a reaction in organic solvent is described below.

1 mol of lactic acid is placed in a mixture composed of 1,000 ml ofdichloromethane and 2 mol of triethanolamine (TEA).

1 mol of stearic acid chloride is then added dropwise to this mixturewith stirring.

After reacting for a few minutes, the solvent is removed by distillationand the product recovered exists in the form of a white powder.

This product comprises, on the one hand, the sought-for lipophilichydroxylated acid comprising anhydride and ester functional groupsbetween the lactic acid and the stearic acid, and the unreacted startingacids.

This product formed by the final reaction mixture can be used as is.

Example 10 of the Invention

Lipophilic Hydroxylated Acid Comprising the Anhydride and EsterFunctional Groups of Lactic Acid and of Stearic Acid

The reaction is carried out as described. in Example 9, except that 2mol of NaH, washed beforehand with hexane, are used in place of 2 mol ofTEA. The reaction is carried out at a temperature close to 0° C.

This product formed by the final reaction mixture can be used as is.

Example 11 of the Invention

Lipophilic Hydroxylated Acid Comprising Amide Bonds by Reaction of aHydroxylated Acid with a Monoamine Containing a C₁₀ -C₃₀ Alkyl Radical

This exale is general for the preparation of lipophilic hydroxylatedacid ccmprising amide bonds.

In general, 1 mol of hydroxylated acid will be placed in a sufficientamount of water which is neutralized to a pH approximately equal to 7. Asufficient amount of phosphate buffer cani be added to the mixture so asto obtain a 0.5M phosphate buffer. 1 mol of a carbodiimide is then addedto the mixture with stirring.

The whole mixture can be stored with stirring for 1 h at roomtemperature or 24 h at 6° C.

1 mol of a monoamine containing a C₁₀ -C₃₀ alkyl radical is then addedto the mixture, with very powerful stirring of the Ultraturrax orSilverson type. After reacting for 4 h at room temperature, the wholemixture is adjusted to a pH of between 2 and 7, and preferably between 3and 6, with 6N HCl.

A lyophilization, and optionally a sterilization with β- or γ-rays, canthen be carried out.

The product obtained can be used as is as active principle of a cosmeticor pharmaceutical or dermatological composition.

It will be noted that the covalent bond which results from this reactionprovides a hydroxylated amide, and other characteristic bonds arepresent between the amine and the hydroxylated acid, such as ionic bondsand bonds of Van der Waals type, which effectively participate in theactivity of the product.

Example 12 of the Invention

Lipophilic Hydroxylated Acid Comprising Amide Functional Groups byReaction of Malic Acid with a Fatty Amine

The reaction is carried out as described in Example 11, except thatmalic acid is used as hydroxylated acid, a fatty amine consisting oflaurylamine or stearylamine is used as amine and a carbodiimideconsisting of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride is used as bifunctional coupling agent.

The reaction mixture can be used as is or in a form which is lyophilizedand optionally sterilized with β- or γ-rays. This can also be carriedout in the context of all the other examples.

Example 13 of the Invention

Lipophilic Hydroxylated Acid Comprising Amide Bonds

Example 13a

The reaction is carried out as described in Example 12 but a carbonatebuffer at a 1M concentration is used as buffer. The carbodiumide and theamine are placed together in the reaction mixture and the pH is adjustedto 7 throughout the reaction.

The final reaction mixture can be used as is.

Example 13b

The reaction is carried out as described in Example 13a but a boratebuffer at a 1M concentration is used.

The final reaction mixture can be used as is.

Example 13c

The reaction is carried out as described in Example 13a but a citratebuffer at a concentration of 0.5M is used.

The final reaction mixture can be used as is.

Example 14 of the Invention

Preparation of Lipophilic Hydroxylated Acid Comprising Amide Bonds

The reaction is carried out as described in

Example 12, except that oxalyl chloride (1 mol) is used as bifunctionalagent in place of a carbodiimide.

The final reaction mixture can be used as is.

Example 15 of the Invention

Enzymatic Preparation of Lipophilic Hydroxylated Acid

100 g of laurylamine are placed to react with 50 g of malic acid and 25g aof an industrial lipase, for example Lipozyme® of Novo®. The reactionis carried out in a closed reactor with stirring at 60° C. for 7 days.The grafting yield is 10% with respect to the starting laurylamine.

The product resulting from this grafting is used as is in the aqueousphase of a cosmetic formulation which can, for example, be produced at apH of 3.

Example 16 of the Invention

Preparation of Lirophilic Hydroxylated Acid Comprising Anhydride andEster Bonds Between Lactic Acid and Palmitic Acid

The same grafting process is used as that described in Example 1 butlactic acid is used in place of malic acid and palmitic acid chloride isused in place of stearic acid chloride.

A palmitic acid and lactic acid ester and anhydride mixture is thusobtained, as well as the unreacted starting acids.

The reaction mixture is advantageously used as is.

It will be observed that in all the preceding examples, as for all theproducts of the invention, these products can be used as activeprinciple of a cosmetic, pharmaceutical and/or dermatologicalcomposition or as emulsifying agent or simultaneously for both thesepurposes.

Tests demonstrating the activities of the products according to theinvention are now described below.

Example 17 of the Invention

Harmlessness Tests by Absence of Skin and Eye Irritation

Harmlessness tests are carried out using the product which has beenlyophilized and sterilized by γ-rays, in the form of a very whitepulverulent powder, obtained in Example 1.

The skin and eye irritation studies are carried out according toprotocols in agreement with EEC directives No. 404 (May 12, 1980) andNo. 405 (Feb. 24, 1987), in the following way:

a) First of all, the pure product is used in the pulverulent form and ata pH of 7.

b) The product obtained is used at a pH of 5.5 in the form of a 20weight % solution in water, which represents 10 weight % of malic acid.

c) The product is used at a pH of 3.5 in the form of a 20 weight %solution, which represents 10 weight % of malic acid.

The adjusting of this pH for each of these products is obtained byvarying the final stage of Example 1. In fact, in Example 1, it isexpected that, after a reaction time of approximately 1 h, the wholemixture is neutralized to a pH of between 2 and 7 with a sodiumhydroxide solution. The pH of the final product can thus be adjusted.

The tests carried out according to the above protocols have made itpossible to observe that the products seem to be non-irritant, wereextremely well tolerated and caused no signs of cutaneous or eyeirritation, whether they are at a pH of 7.5, 5 or even 3.5.

Moreover, oral administration of a maximum dose of 5 g of the product ofthe invention of Example 1 per kilogram of body weight caused notoxicity, this test being carried out in accordance with the EECprotocol relating to the study of oral toxicity of the EEC directive No.401 of Feb. 24, 1987.

Example 18 of the Invention

In Vivo Allergy Test on Animals

Experimental Protocol

The test is carried out according to the experimental protocol describedbelow, adapted from the method described by Magnusson and Kligma (J.Invest. Derm., 1969, 52, 268-276), which is recognized by the personskilled in the art as a reliable and reproducible method.

1.--Characterization of the Experimental Model

1.1--Animals Used

albino guinea pigs, Hartley strain, provided by the firm Maury (24610Villefranche de Lonchat, France),

weighing approximately 350 g at the beginning of the test,

identified by individual branding with picric acid.

Before the test, the animals are kept for 6 days under the sameconditions as during the test.

1.2--Caging

The animals are kept in 3 46.5 cm×31 cm×19 cm Makrolon boxes, the floorsof which are covered with clean sawdust.

A device for supplying food to the guinea pig and a feedbottle areattached to the lid which forms a grid made of stainless steel.

The boxes are kept in a room:

lit complementarily with natural and artificial light,

with air conditioning: renewal of the air takes place 14 cycles perhour, the temperature is maintained at 22° C.±1° (upper and lowerlimit), and the relative humidity is maintained at 52%±8 (upper andlower limit).

1.3--Food

Animals receive tap water and food.

2--Test conditions

2.1--Determination of the maximum Non-irritatant Concentration byTopical Application

This test is carried out with 3 guinea pigs which received an injectionof Freund's adjuvant 3 weeks previously. The different concentrationstested under semi-absorbent compress were 1/1, 1/2, 1/4 and 1/8.Dilutions were carried out with distilled water.

2.2--Determination of the Maximum Irritating Concentration byIntradermal Injection

This control was not carried out due to the fact that the inductionphase can be carried out with undiluted product.

2.3--Final Study

It was carried out on 30 animals in groups of 15:

GROUP 1 (control)

GROUP 2 (treated).

INDUCTION PHASE

It was carried out as follows:

Treated group: The following operations are carried out on all theanimals in the scapular region on both sides of the vertebral axis:

A D0:

Injection of 0.1 ml of 50% Freund's adjuvant in isotonic NaCl.

Injection of 0.1 ml of undiluted product.

Injection of 0.1 ml of a mixture of equal volumes of product and ofFreund's adjuvant.

A D7:

Application to the region of the injections of 1 ml of 10% sodium laurylsulfate in petrolatum.

A D8:

Application for 48 hours under semi-absorbent compress of 0.5 ml of theproduct as is.

Control group:

The animals of this group receive the same treatment as those of thetreated group but a saline solution is used in place of the product.

The animals of the two groups are then kept for 2 weeks.

CHALLENGE PHASE

On day D27, after they have been carefully restrained by restrainingdevices, the animals of the two groups receive, on a posterior region ofthe back, 0.5 ml of the test product consisting of the product of theinvention obtained in Example 1, that is to say malic acid, at itsmaximum non-irritant concentration (MNIC) dose and at its MNIChalf-dose, under semi-absorbent compress for 24 hours.

2.4--Macroscopic Observations

Erythema and/or edema are recorded 24 and 48 hours after removing thepad or patch.

The scores are allocated according to the following grading scale:

    ______________________________________                                               No reaction                                                                             0                                                              Slight reaction 1                                                             Moderate reaction 2                                                           Major reaction 3                                                            ______________________________________                                    

Erythema and edema are recorded according to the same grading scale.

2.5--Interpretation of the results

The scores obtained for erythema and edema are added.

All the animals which show a score equal to or greater than 2 after thechallenge phase are regarded as being positive.

All the other signs (such as stingings, blisters, and the like) are alsotaken into consideration in the interpretation.

The sensitizing ability is defined by the percentage of positive animalsaccording to the following scale:

    ______________________________________                                        Percentage     Class  Classification                                          ______________________________________                                        0-8            I      Very light                                                 9-28 II Light                                                                29-64 III Moderate                                                            65-80 IV Strong                                                                81-100 V Very strong                                                       ______________________________________                                    

RESULTS

1--Concentrations to Used

For the induction: 1/1

For the challenge phase: 1/1 (MNIC) and 1/2 (1/2 MNIC)

2--Determination of a Sensitizing Ability

All microscopic reaction was recorded, both in the control group and inthe treated group, whatever the concentration used.

CONCLUSION

Under the experimental conditions employed, the product of theinvention, lipophilized malic acid according to the invention used at20% in distilled water, did not induce a macroscopic reaction whichcould be related to a sensitization in albino guinea pigs.

The product can conseqently be regarded as being hypoallergenic.

Example 19 of the Invention

In Vivo Tests of Keratolytic Activity on Adult Caucasian Volunteers

A--Method

In order to determine the keratolytic activity of the lipophilizedhydroxylated acids according to the invention, cosmetic formulationscontaining increasing amounts of lipophilized hydroxylated acidsaccording to the invention were prepared and then tested on panels of 10volunteers of adult Caucasian type. Each panel compared a keratolyticformula to the corresponding placebo formula. An untreated site wasretained for comparison. The test was carried out on circular regionswith a diameter of 25 mm, delimited on the inner face of the forearmsusing self-adhesive rings. These regions had been impregnated beforehandon three occasions and at intervals of 6 h with a cosmetic formulationcontaining 10% dihydroxyacetone.

The creams tested were delivered in a fixed amount of 1 ml on day 1, 3,5, 7, 10 and 12. The regions concerned are covered for 1/2 hour with anabsorbent aerated compress which absorbs the excess product. Thedifferences in coloring are noted visually before each application.

B--Compositions Tested

The compositions tested during this study are the following:

1--a placebo composition, prepared at a pH of 5.5, which does notcontain keratolytic agent and which has the following percentageformulation:

    ______________________________________                                        Phase A                                                                         Sodium dihydroxycetyl phosphate (and) 2%                                      isopropyl hydroxycetyl ether                                                  Glycerol 3%                                                                   Propylene glycol 2%                                                           Water qs for 100%                                                             Phase B                                                                       Glycol stearate 14%                                                           Triisononanoin 5%                                                             Octyl cocoate 6%                                                              Phase C                                                                       Bactericidal agent based on butylene glycol and parabens 1%                   commercially available under the name Bactericide MB,                         company DRAGOCO                                                               Phenoxyethanol and parabens 1%                                              ______________________________________                                    

This placebo composition is prepared conventionally by emulsifying PhaseB in Phase A with stirring and by then adding the bactericidal agent ofPhase C.

2--Composition A₁, prepared at a pR of 5.5, Containing 4% Malic Acid

The preparation of this composition A₁ is as described for themanufacture of the placebo composition but Phase A contains 4% of malicacid.

3--Compositions of the invention I₁, I₂, I₃

These compositions I₁, I₂, I₃ are prepared as described for the placebocomposition, except that Phase A contains increasing amounts of thecompound according to the invention of Example 1 comprising a stearicacid/malic acid anhydride and ester bond mixture, the equivalentconcentration of the malic acid part in the compound of the inventionrepresenting respectively 2%, 4% and 6% of the compositions I₁, I₂, I₃.The two compositions are also prepared at pH 5.5.

In order to adjust the pH to 5.5 for each of these placebo, A₁ and I₁,T₂ and I₃ compositions, the pH is adjusted using concentratedhydrochloric acid or concentrated sodium hydroxide solution.

C--Results

Repeated applications of a formulation based on dihydroxyacetone (DRA)makes it possible to color the upper layers of the skin as would a"self-tanning" product. The decoloring of a region thus treated requires15 days. The application to such a region of a cosmetic formulationcontaining a keratolytic active agent will make it possible to obtain afaster decoloring. Measuring this decoloring every three days for 15days makes it possible to study the keratolytic power of the activeprinciples studied.

Such a decoloring is measured with a Minolta chromameter. The lightparameters L, a and b are calculated in the form of a mean of 5experimental data for each subject and for each period monitored.

The mean color difference ΔE*ab=(ΔL² +Δa² +Δb²)^(1/2) is calculatedbetween each site treated and the control region (colored with DEA butnot treated with one of the compositions).

If T₀ is the beginning of the experiment and T_(F) the finish of theexperiment (see FIG. 1), ΔE represents the variation in color intensitybetween the control region defined by Curve I, in this case consistingof a straight line, extending from the color intensity point C₀ at T₀ tothe color intensity point C_(F) at T_(F), and a zone treated with akeratolytic composition defined by Line II, FIG. 1, in this case alsoconsisting of a straight line extending from the color intensity pointC₀ to the color intensity point C_(F), which is in this case obtained attime T.sub.ΔEmax. This variation should increase to a maximum (ΔE_(max))achieved for T.sub.ΔEmax and should then decrease.

Such variations depend on the keratolytic property of each composition.The surface between the two curves is directly proportional to thekeratolytic power intensity of each composition.

Thus, applications of the compositions indicated above, respectively theplacebo composition, the comparison composition A, and the compositionsof the invention I₁, I₂, I₃, according to the method described above,make it possible to observe the following results:

a) The placebo composition causes the disappearance of part of thecoloring, which is notable from the 8th day. This observation isconfirmed throughout the 15 days of the experiment required forobtaining complete decoloring. This means that this preparation has aweak but real keratolytic power. This power may arise from the massagingduring the application of the cream as well as from the moisturing powerof the cream which, by detaching the corneocytes, thus makes possible aslightly faster than normal desquamation.

b) The four keratolytic compositions, A₁, I₁, I₂, and I₃ respectively,are very strongly keratolytic. In fact, 7 days after the beginning ofthe tests, the decoloring is already virtually complete, which meansthat the time required for causing desquamation of the colored layers ishalved, from 15 days to 7 days. This result is confirmed by themeasurement with a chromameter with respect to time.

The measurements with the chromameter obtained with respect to time foreach of the compositions tested, A₁, I₃, I₂ and I₃, are recorded inTable I below, expressed as mean color intensity difference ΔE inaccordance with the standard of FIG. 1.

                                      TABLE I                                     __________________________________________________________________________                                            Sum                                             D3 to                                                                 Emulsion containing Time D3 D5 D7 D10 D12 D15 D15                           __________________________________________________________________________    Nothing (placebo)  Mean                                                                             0.87                                                                             1.20                                                                             0.95                                                                             1.24                                                                             0.34                                                                             0.03                                                                             4.64                                     SD* 0.39 0.45 0.25 0.41 0.58 0.22 2.29                                       Lipophilized malic acid, corresponding to a Mean 2.94 3.90 3.87 3.20                                                1.43 0.36 15.70                         2% concentration of free malic acid (I.sub.1) SD* 0.99 1.13 0.86 0.77                                               0.61 0.44 4.80                          Lipophilized malic acid, corresponding to a Mean 4.93 6.99 8.26 7.64                                                4.76 0.94 33.52                         4% concentration of free malic acid (I.sub.2) SD* 0.84 0.97 1.16 1.50                                               1.75 0.75 6.97                          Lipophilized malic acid, corresponding to a Mean 4.70 6.80 7.71 7.04                                                4.87 1.29 32.40                         6% concentration of free malic acid (I.sub.3) SD* 1.05 1.14 0.68 1.12                                               1.54 1.28 6.81                          Free malic acid at a concentration of 4% Mean 4.58 6.73 7.63 6.93 4.98                                              1.80 32.64                              in the formulation (A.sub.1) SD* 1.05 1.21 1.05 1.12 1.44 1.29 7.17         __________________________________________________________________________     SD* = Standard Deviation                                                 

By way of example, the color intensity differences obtained with thecomposition of the invention I₂ are recorded in bar chart form in FIG.2, the color intensity differences ΔE being represented in black and thestandard deviation SD being added in the form of a gray bar.

In addition, the sum of all the color intensity differences ΔE obtainedwith the placebo composition and the compositions of the invention, I₁,I₂ and I₃, are recorded in FIG. 3 with respect to the equivalentconcentration of free malic acid, in black, the standard deviation SDbeing added in gray.

It should be noted that the test results obtained with 4% free malicacid in positive control form mentioned in Table I are not shown in FIG.3 since the bars obtained are essentially identical to those of thecomposition of the invention I₂ and cannot be differentiated from thelatter.

From these test results, it may be observed that, for the sameequivalent concentration of malic acid, the composition containinglipophilized malic acid (I₂) has a keratolytic power or intensity whichis as strong as the composition containing free malic acid (A₁) .

The lipophilized malic acid according to the invention and described inExample 1 of the present invention has a keratolytic power or intensityas strong as free malic acid.

c) Among the two keratolytic compositions, A₁ and I₂ respectively,composition I₂, prepared with lipophilized lactic acid according to thepresent invention, was perfectly well tolerated by the variousvolunteers and caused no stinging, no irritation and no inflammationwhereas stinging and blotches were perceptible in the case of the freemalic acid used in the formulation of the composition A₁.

d) Among all the keratolytic compositions containing lipophilized malicacid, that is to say I₁ (4.3% of lipophilized malic acid, correspondingto an equivalent concentration of malic acid of 2%), 12 (8.7% oflipophilized malic acid, corresponding to an equivalent concentration ofmalic acid of 4%) and I₃ (13% of lipophilized malic acid, correspondingto an equivalent concentration of malic acid of 6%), I₂ and I₃ are themost powerful keratolytic compositions (see FIG. 3).

On increasing the concentration of lipophilized malic acid in thecompositions, an increase in the keratolytic properties of suchcompositions is obtained.

Such an increase is stabilized at a plateau for high concentrations,very probably due to a maximum storage capacity of the skin.

A description is now given below of various cosmetic or pharmaceuticaland/or dermatological composition formulation examples.

Example 20 of the Invention

Cosmetic composition possessing a keratolytic effect

This composition has the following percentage composition:

    ______________________________________                                        Malic acid/stearic acid lipophilic                                                               10%                                                          hydroxylated acid of Example 1                                                Salicylic acid 0.5%                                                           Urea  4%                                                                      Cosmetic excipient q.s. for 100%                                            ______________________________________                                    

Example 21 of the Invention

Cosmetic composition possessing an anti-acne effect

This composition has the following percentage composition:

    ______________________________________                                        Salicylic acid/undecylenic acid lipophilic                                                          4%                                                        hydroxylated acid of Example 4                                                Pharmaceutical excipient q.s. for 100%                                      ______________________________________                                    

Example 22 of the Invention

Cosmetic composition possessing an anti-dandruff activity

This composition has the following ingredients in percentage by weight:

    ______________________________________                                        Lipophilic hydroxylated acid of                                                                    10%                                                        Example 16 (malic acid/laurylamine)                                           Pharmaceutical excipient q.s. for 100%                                      ______________________________________                                    

Example 23 of the Invention

Moisturizing pharmaceutical composition

    ______________________________________                                        Lipophilic hydroxylated acid of Example 6                                                           5%                                                        (serine/linolenic and stearic acid)                                           Urea 2%                                                                       Cosmetic excipient q.s. for 100%                                            ______________________________________                                    

Example 24 of the Invention

Pharmaceutical composition for treating ichthyotic skins, psoriasis oreczemas

    ______________________________________                                        Lipophilic hydroxylated acid of Example 4                                                           6%                                                        (salicylic acid/undecylenic acid)                                             Lipophilic hydroxylated acid of Example 2 6%                                  (glycolic acid/palmitic acid)                                                 Pharmaceutical excipient q.s. for 100%                                      ______________________________________                                    

Example 25 of the Invention

Restructuring anti-age formulation

    ______________________________________                                        Phases                       Amounts (%)                                      ______________________________________                                        A/     Ether of polyethylene glycol (2)                                                                    3                                                   and of stearyl alcohol                                                        Ether of polyethylene glycol 2                                                (21) and of stearyl alcohol                                                   Isostearyl isostearate 4                                                      Apricot kernel oil 4                                                          Safflower oil 2                                                               Dimethicone 556 2                                                             Cetostearyl alcohol 3                                                        B/ Glycerol 5                                                                  Lipophilic hydroxylated acid of 6                                             Example 1 (malic acid/stearic acid)                                           Water q.s. for 100                                                           C/ Phenoxyethanol and mixture of parabens 0.5                                  Propylene glycol 0.5                                                         D/ Phenoxyethanol 0.3                                                          α-Tocopherol 0.05                                                    ______________________________________                                    

Phases A and B are heated separately to 75° C. with moderate stirring.The pH of Phase B is adjusted to the desired pH value. A is poured intoB with very vigorous stirring (of the Silverson or Ultraturrax type) andthen the temperature is allowed to fall with slow stirring. Thecomponents of Phases C and D are added at 30° C.

Example 26 of the Invention

Anti-wrinkle formulation

    ______________________________________                                        Phases                       Amounts (%)                                      ______________________________________                                        A/     Isostearyl isostearate                                                                              4                                                   Safflower oil 4                                                               Oleyl erucate 2                                                               Dimethicone 5                                                                 Cetostearyl alcohol 3                                                         Lipophilic hydroxylated acid of 3                                             Example 1 (malic acid/stearic acid)                                          B/ Glycerol 5                                                                  Water q.s. for 100                                                           C/ Phenoxyethanol and mixture of parabens 0.5                                  Propylene glycol 0.5                                                         D/ Phenoxyethanol 0.3                                                       ______________________________________                                    

Phases A and B are heated separately to 75° C. with moderate stirring.The pH of the formula is conditioned in this case by the pH of thelipophilic hydroxylated acid. A is poured into B with very vigorousstirring (of the Silverson or Ultraturrax type) and the temperature isthen allowed to fall with slow stirring. The components of Phases C andD are added at 30° C. If necessary, the preparation is adjusted to thedesired pH using, for example, lactic acid.

It should be noted that the product of the invention is also used asemulsifying agent in this formulation.

Example 27 of the Invention

Face, dry skins formulation

    ______________________________________                                        Phases                       Amounts (%)                                      ______________________________________                                        A/     Borage oil            2                                                   Safflower oil 4                                                               Caprylic/capric triglyceride 6                                                Cetostearyl alcohol 3                                                        B/ Glycerol 5                                                                  Water q.s. for 100                                                            Lipophilic hydroxylated acid of 4                                             Example 2 (glycolic acid/palmitic acid)                                      C/ Phenoxyethanol and mixture of parabens 0.5                                  Propylene glycol 0.5                                                         D/ Phenoxyethanol 0.3                                                       ______________________________________                                    

Phases A and B are heated separately to 75° C. with moderate stirring.The pH of Phase B is adjusted to the desired pH of the formulation. A ispoured into B with very vigorous stirring (of the Silverson orUltraturrax type) and the temperature is then allowed to fall with slowstirring. The components of Phases C and D are added at 30° C. Ifnecessary, the preparation is adjusted to the desired pH using, forexample, lactic acid.

It should be noted that the product of the invention is also used asemulsifying agent in the formulation (absence of other emulsifyingagents in the formula).

What is claimed is:
 1. A lipophilic salicylic acid compound which is thereaction product of salicylic acid with at least one hydrophobichydrocarbon compound selected from the group consisting of a halide oranhydride of stearic acid, a halide or anhydride of palmitic acid, ahalide or anhydride of myristic acid, a halide or anhydride of lauricacid, a halide or anhydride of undecylenic acid, a halide or anhydrideof oleic acid, a halide or anhydride of linoleic acid, and a halide oranhydride of linolenic acid, wherein said lipophilic salicylic acidcompound is in a final reaction mixture of the lipophilic salicylic acidcompound with the unreacted salicylic acid and the unreacted hydrophobichydrocarbon compound, and the ratio by weight of the salicylic acid tothe hydrophobic hydrocarbon compound ranges between 0.05 and
 10. 2. Acomposition comprising as active ingredient a lipophilic salicylic acidcompound which is the reaction product of salicylic acid with at leastone hydrophobic hydrocarbon compound selected from the group consistingof a halide or anhydride of stearic acid, a halide or anhydride ofpalmitic acid, a halide or anhydride of myristic acid, a halide oranhydride of lauric acid, a halide or anhydride of undecylenic acid, ahalide or anhydride of oleic acid, a halide or anhydride of linoleicacid, and a halide or anhydride of linolenic acid, wherein saidlipophilic salicylic acid compound is in a final reaction mixture of thelipophilic salicylic acid compound with the unreacted salicylic acid andthe unreacted hydrophobic hydrocarbon compound, and the ratio by weightof the salicylic acid to the hydrophobic hydrocarbon compound rangesbetween 0.05 and
 10. 3. A cosmetic composition comprising as activeingredient a lipophilic salicylic acid compound which is the reactionproduct of salicylic acid with at least one hydrophobic hydrocarboncompound selected from the group consisting of a halide or anhydride ofstearic acid, a halide or anhydride of palmitic acid, a halide oranhydride of myristic acid, a halide or anhydride of lauric acid, ahalide or anhydride of undecylenic acid, a halide or anhydride of oleicacid, a halide or anhydride of linoleic acid, and a halide or anhydrideof linolenic acid, in a cosmetically acceptable excipient, wherein saidlipophilic salicylic acid compound is in a final reaction mixture of thelipophilic salicylic acid compound with the unreacted salicylic acid andthe unreacted hydrophobic hydrocarbon compound, and the ratio by weightof the salicylic acid to the hydrophobic hydrocarbon compound rangesbetween 0.05 and
 10. 4. A pharmaceutical composition comprising asactive ingredient a lipophilic salicylic acid compound which is thereaction product of salicylic acid with at least one hydrophobichydrocarbon compound selected from the group consisting of a halide oranhydride of stearic acid, a halide or anhydride of palmitic acid, ahalide or anhydride of myristic acid, a halide or anhydride of lauricacid, a halide or anhydride of undecylenic acid, a halide or anhydrideof oleic acid, a halide or anhydride of linoleic acid, and a halide oranhydride of linolenic acid, in a pharmaceutically acceptable excipient,wherein said lipophilic salicylic acid compound is in a final reactionmixture of the lipophilic salicylic acid compound with the unreactedsalicylic acid and the unreacted hydrophobic hydrocarbon compound, andthe ratio by weight of the salicylic acid to the hydrophobic hydrocarboncompound ranges between 0.05 and 10, and wherein the proportion of thelipophilic salicylic acid compound ranges between 0.01 weight percentand 50 weight percent with respect to the total weight of the finalcomposition.
 5. A lipophilic salicylic acid compound which is thereaction product of salicylic acid with undecylenic acid chloride oranhydride, wherein said lipophilic salicylic acid compound is in a finalreaction mixture of the lipophilic salicylic acid compound with theunreacted salicylic acid and the unreacted undecylenic acid, and theratio by weight of the salicylic acid to the undecylenic acid chlorideor anhydride ranges between 0.05 and
 10. 6. A composition whichcomprises as active ingredient a lipophilic salicylic acid compoundwhich is the reaction product of salicylic acid with undecylenic acidchloride or anhydride, wherein said lipophilic salicylic acid compoundis in a final reaction mixture of the lipophilic salicylic acid compoundwith the unreacted salicylic acid and the unreacted undecylenic acid,and the ratio by weight of the salicylic acid to the undecylenic acidchloride or anhydride ranges between 0.05 and
 10. 7. A cosmeticcomposition which comprises a cosmetically effective amount of alipophilic salicylic acid compound which is the reaction product ofsalicylic acid with undecylenic acid chloride or anhydride, in acosmetically acceptable excipient, wherein said lipophilic salicylicacid compound is in a final reaction mixture of the lipophilic salicylicacid compound with the unreacted salicylic acid and the unreactedundecylenic acid, and the ratio by weight of the salicylic acid to theundecylenic acid chloride or anhydride ranges between 0.05 and
 10. 8. Acomposition comprising the compound of claim 1, wherein the compositionis in a lyophilized form.
 9. A cosmetic or pharmaceuitical compositioncomprising the lipophilic acid compound of claim 1, wherein saidlipophilic salicylic acid compound is present in the composition at aconcentration ranging between 0.1 weight percent and 50 weight percentwith respect to the total weight of the final composition.
 10. Acosmetic or pharmaceutical composition comprising the lipophilic acidcompound of claim 1, wherein said lipophilic salicylic acid compound ispresent in the composition at a concentration ranging between 1 weightpercent and 10 weight percent with respect to the total weight of thefinal composition.
 11. The compound of claim 1, wherein the ratio byweight of the salicylic acid to the hydrophobic hydrocarbon compoundranges between 0.05 and
 2. 12. An emulsifier comprising the compound ofclaim
 1. 13. The composition of claim 3, wherein the proportion of thelipophilic salicylic acid compound ranges between 1 weight percent and20 weight percent with respect to the total weight of the finalcomposition.
 14. The compound of claim 5, wherein said final reactionmixture of the lipophilic salicylic acid compound with the unreactedsalicylic acid and the unreacted undecylenic acid has been neutralizedat a pH ranging between 2.0 and 7.0 by a neutralizing agent.
 15. Acomposition comprising the compound of claim 5, wherein the compositionis in a lyophilized form.
 16. The compound of claim 5, wherein the ratioby weight of the salicylic acid to the undecylenic acid compound rangesbetween 0.05 and
 2. 17. The composition of claim 4, wherein saidlipophilic salicylic acid compound is present at a concentration rangingbetween 1 weight percent and 20 weight percent with respect to the totalweight of the final composition and said final reaction mixture is underneutralized form.
 18. A composition comprising the compound of claim 7,wherein the composition is in a lyophilized form.
 19. A cosmetic orpharmaceutical composition comprising the lipophilic acid compound ofclaim 7, wherein said lipophilic salicylic acid compound is present inthe composition at a concentration ranging between 0.1 weight percentand 50 weight percent with respect to the total weight of the finalcomposition.
 20. A cosmetic or pharmaceutical composition comprising thelipophilic acid compound of claim 7, wherein said lipophilic salicylicacid compound is present in the composition at a concentration rangingbetween 1 weight percent and 10 weight percent with respect to the totalweight of the final composition.
 21. The compound of claim 7, whereinthe ratio by weight of the salicylic acid to the hydrophobic hydrocarboncompound ranges between 0.05 and
 2. 22. The compound of claim 7, whereinsaid final reaction mixture of the lipophilic salicylic acid compoundwith the unreacted salicylic acid and the unreacted undecylenic acid hasbeen neutralized at a pH ranging between 2.0 and 7.0 by a neutralizingagent.
 23. The composition of claim 3, wherein said lipophilic salicylicacid compound is present at a concentration ranging between 1 weightpercent and 20 weight percent with respect to the total weight of thefinal composition and said final reaction mixture is under neutralizedform.